Synthesis of 2-carboxamide cycloamino urea derivatives

Abstract

Provided herein are processes useful for the preparation of 2-carboxamide cycloamino urea derivatives of formula (X), and useful intermediates therefore, at internal temperatures such as less than about −5° C. to about −15° C. and using solvents such as tetrahydrofuran, bases such as amines, and the like.

The invention claimed is: 
     
       1. A process for making a compound of formula (X): 
       
         
           
           
               
               
           
         
         comprising the following steps: 
         Step A: contacting a compound of formula (I) with the solvent tetrahydrofuran and a base lithium diisopropylamide at an internal temperature in the range of −15° C. to less than −5° C., and contacting the resulting mixture with a compound of formula (II) at an internal temperature in the range of −15° C. to less than −5° C., such that a compound of formula (III) is produced: 
       
       
         
           
           
               
               
           
         
         Step B: contacting a compound of formula (III) with thiourea, in a reaction mixture comprising a solvent selected from toluene, an alcohol solvent, or a combination thereof and an oxidizing agent N-bromosuccinimide or 1,3-dibromo-5,5-dimethylhydantoin, such that a compound of formula (V) is produced: 
       
       
         
           
           
               
               
           
         
         Step C: contacting a compound of formula (V) with a compound of formula (VII), in a reaction mixture comprising the solvent tetrahydrofuran and a base amine, such that a compound of formula (VIII) is produced: 
       
       
         
           
           
               
               
           
         
         Step D: contacting a compound of formula (VIII) with the compound of formula (IX) 
       
       
         
           
           
               
               
           
         
       
       in a reaction mixture comprising a solvent selected from tetrahydrofuran, water or a combination thereof, such that a compound of formula (X) is produced,
 wherein: 
 R 1  is a branched or linear C 1 -C 7  alkyl, which may be optionally substituted one or more times with deuterium, halogen, or C 3 -C 5  cycloalkyl; 
 R 2  is methyl; 
 R 3  is C 6 -C 14  aryloxy, 
 R 4  is halogen, and 
 X is a halide. 
 
     
     
       2. The process of  claim 1 , wherein the solvent of Step B comprises toluene and ethanol. 
     
     
       3. The process of  claim 1  wherein the base of Step C is pyridine. 
     
     
       4. The process of  claim 1 , wherein the oxidizing agent of Step B is N-bromosuccinimide. 
     
     
       5. The process of  claim 1  wherein the solvent of Step A comprises tetrahydrofuran, the base of Step A is lithium diisopropylamide, the solvent of Step B comprises toluene and ethanol, the oxidizing agent of Step B is N-bromosuccinimide, the solvent of Step C comprises tetrahydrofuran, the base of Step C is pyridine and the solvent of Step D comprises tetrahydrofuran and water. 
     
     
       6. The process of  claim 1 , wherein R 1  is 
       
         
           
           
               
               
           
         
       
       R 2  is methyl, R 3  is phenoxy, R 4  is chlorine, and X is bromine. 
     
     
       7. A process for making the compound of formula (10): 
       
         
           
           
               
               
           
         
         comprising the following steps: 
         Step A: contacting the compound of formula (1) with the solvent tetrahydrofuran and a base lithium diisopropylamide at an internal temperature in the range of −15° C. to less than −5° C., and contacting the resulting mixture with the compound of formula (2) at an internal temperature in the range of −15° C. to less than −5° C., such that the compound of formula (3) is produced: 
       
       
         
           
           
               
               
           
         
         Step B: contacting the compound of formula (3) with thiourea, in a reaction mixture comprising a solvent selected from toluene, ethanol or a combination thereof and an oxidizing agent N-bromosuccinimide, such that the compound of formula (5) is produced: 
       
       
         
           
           
               
               
           
         
         Step C: contacting the compound of formula (5) with the compound of formula (7), in a reaction mixture comprising the solvent tetrahydrofuran and a base amine, such that the compound of formula (8) is produced: 
       
       
         
           
           
               
               
           
         
       
       and
 Step D: contacting the compound of formula (8) with the compound of formula (IX) 
 
       
         
           
           
               
               
           
         
       
       in a reaction mixture comprising a solvent selected from tetrahydrofuran, water or a combination thereof, such that the compound of formula (10) is produced. 
     
     
       8. The process of  claim 1 , wherein the resulting mixture of a compound of formula (I) and the solvent tetrahydrofuran and base lithium diisopropylamide of Step A is contacted with a compound of formula (II) at an internal temperature of −15° C. 
     
     
       9. The process of  claim 1  wherein the solvent of Step D comprises tetrahydrofuran and water. 
     
     
       10. The process of  claim 7 , wherein the resulting mixture of a compound of formula (1) and the solvent tetrahydrofuran and base lithium diisopropylamide of Step A is contacted with a compound of formula (2) at an internal temperature of −15° C. 
     
     
       11. The process of  claim 1 , wherein the solvent of step A is an alcohol solvent, wherein the alcohol solvent is ethanol.